The long term objectives of this research proposal are to define the oncogene-induced pathways that promote myeloid cell leukemogenesis. Although the oncoprotein c-Myc, which promotes cell cycle progression, is constitutively activated in many leukemia and lymphomas, it also is a potent inducer of apoptosis. Preliminary investigations into Myc-induced apoptosis have suggested that Myc influences the expression of proteins that regulate apoptosis. Myc selectively suppresses Bcl-2, an anti-apoptotic protein, in immortal IL-3-dependent myeloid cell lines, whereas Myc induces the tumor suppressors p19ARF and p53 in fibroblasts. Creating a mouse model of myeloid leukemia by generating a myeloid cell-specific Myc transgenic mouse will provide an essential resource to test our hypothesis that a relationship exists between myc-induced apoptosis and transformation. The myeloid cell-specific Myc Tg mice crossed to Bcl-2, Bax-, p19ARF-, and p53-null mice will elucidate the contribution these proteins have to Myc-induced myeloid cell death and tumorigenesis. These studies will further our understanding of Myc-induced myeloid cell transformation and how apoptotic pathways influence this process.